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Complex hierarchical organization is a hallmark of tissues and their subsequent integration into organs. A major challenge in tissue engineering is to generate arrays of cells with defined structural organization that display appropriate functional properties. Given what is known about cellular responses to physiochemical cues from the surrounding environment, we can build tissue structures that mimic these microenvironments and validate these platforms using both experimental and computational approaches. Tissue generation encompasses many methods and tissue types, but here we review layering cell sheets to create scaffold-less myocardial patches. We discuss surgical criteria that can drive the design of myocardial cell sheets and the methods used to fabricate, mechanically condition, and functionally test them. We also focus on how computational and experimental approaches could be integrated to optimize tissue mechanical properties by using measurements of biomechanical properties and tissue anisotropy to create predictive computational models. Tissue anisotropy and dynamic mechanical stimuli affect cell phenotype in terms of protein expression and secretion, which in turn, leads to compositional and structural changes that ultimately impact tissue function. Therefore, a combinatorial approach of design, fabrication, testing, and modeling can be carried out iteratively to optimize engineered tissue function.

Engineering Myocardial Tissue Patches with Hierarchical Structure–Function